The present invention relates to stabilized formulations of acid-labile drugs that provide a delayed and rapid release of the drug into the gastrointestinal tract. More particularly, the invention relates to an omeprazole formulation comprising a thick coating not containing a conventional enteric release polymer.
Omeprazole is the first of a new class of drugs that inhibits gastric secretion by altering the activity of H+/K+ ATPase, the final common step of acid secretion in gastric parietal cells. Omeprazole is indicated as therapy for short-term treatment of active duodenal ulcers and is also used in the treatment of severe erosive esophagitis or poorly responsive symptomatic gastroesophageal reflux disease (GERD).
The plasma half-life of omeprazole is about 60 minutes; however, the duration of action of a single-dose may exceed 24 hours. The recommended dose of omeprazole is 20 mg daily for 4-8 weeks that may be repeated, if necessary.
Pilbrant and Cederberg (1985) reported on the physical and chemical properties of omeprazole. The drug has low water solubility and is chemically unstable in an acidic environment. Omeprazole degrades very rapidly in acidic aqueous solutions, and the rate of degradation proceeds with a half-life of less than 10 minutes, at pH values below 4. Although it is very slightly soluble in water, the drug is very soluble in alkaline solution as the negatively charged ion. At pH 6.5, the half-life of degradation was reported to be about 18 hours, and at pH 11, the half-life extends to several hundred days. Preformulation studies indicated that moisture, solvents, and acidic substances had a deleterious effect on the stability of omeprazole.
The resting pH of the stomach is generally less than 2 and a meal may increase the pH to between 3 and 5. The major physiological stimulus for acid secretion in the stomach is the ingestion of food, especially if the meal has a high protein content. It is the protein component of the meal that possesses the greatest buffering capacity. Foods, such as milk, can raise the gastric pH to values as high as 6. Gastric emptying times can show considerable variation between subjects according to the test methods used, and can generally vary between 0.5-2.0 hours.
To protect omeprazole from the hostile environment of the stomach, Pilbrant and Cederberg, and others, have applied an enteric coat to solid substrates, such as granules, containing omeprazole prior to conducting bioavailability studies in humans. A fully bioavailable dosage form for omeprazole must release the active drug rapidly in the proximal part of the gastrointestinal tract.
In U.S. Pat. No. 4,786,505, Lovgren et al disclose a pharmaceutical preparation containing omeprazole and salts together with other alkaline compounds. A core containing omeprazole is surrounded by an enteric release coating. A subcoating, that is water soluble or rapidly disintegrating in water, separates the core from the enteric coat that protects the preparation from the hostile environment of the stomach. Enteric coatings are also disclosed in U.S. Pat. No. 5,385,739. The subcoat or separating layer in the ""505 patent and in U.S. Pat. No. 4,853,230, also serves to separate the omeprazole from the acidic pH environment of the enteric polymers, i.e., enteric polymers are generally applied as a solution to a core containing a drug. Such enteric polymers are generally acidic, and therefore are capable of degrading omeprazole in the core during application of the coating to the core. Conventional enteric polymers may include shellac, Eudragit(trademark) L100 and S100, Eudragit(trademark) L30D 55 and Eudragit FS30D, cellulose acetate phthalate, PVAP, HPMCAS and HPMCP, or similar materials that are insoluble in acidic environments or water and pass into solution at pH values above pH 5.0, the pH of the upper GI tract downstream from the stomach. Each of these references discloses that a separating layer must be used between the enteric coat and the core and that an enteric coat must be used in order to provide a suitable release profile. However, given the tendency of enteric release polymers to degrade omeprazole, a subcoating is required. The requirement for a subcoating unnecessarily complicates manufacture of a stabilized dosage form. The subcoating in these formulations does not delay release of the omeprazole from the core to any significant extent.
None of the known omeprazole formulations have employed non-enteric coatings, i.e., coatings that do not rely upon pH changes that occur in the GI tract, to effect a delayed and subsequently rapid release of omeprazole. Use of only a non-acidic non-enteric coating to effect the delayed and rapid release of omeprazole would be beneficial as it would simplify the method for manufacturing a stabilized dosage form.
The present invention seeks to overcome at least some of the above-mentioned disadvantages inherent in known omeprazole-containing formulations. Stable and bioavailable omeprazole solid dosage forms are disclosed herein. Accordingly, one aspect of the invention provides a stabilized formulation containing omeprazole, or a salt thereof, wherein the formulation does not require a separating layer or an enteric release coating. The present formulation provides a physically and chemically stable delivery system for omeprazole and its salts, maintains drug stability during storage, stabilizes omeprazole in the acidic portions of the GI tract of a patient, and provides a rapid release of omeprazole in the upper GI tract. The formulation of the invention does not require or include an enteric coating or a separating layer to protect the omeprazole in the core of the tablet.
The present omeprazole formulation can exist as any multiparticulate form such as granules, spheroids, microspheres, seeds, pellets, beads, microcapsules, agglomerates, mini-tablets or tablets that are manufactured employing conventional techniques and pharmaceutical excipients. The formulation optionally contains an alkalizing agent present in the core of the dosage form and/or in the non-enteric coating surrounding the core.
Instead of an enteric coating, the formulation of the invention includes a non-enteric time-release (TR) coating applied directly over the omeprazole-containing core. This coating can be applied using conventional or perforated coating pans, fluidized bed equipment or by compression coating. The composition of this coating is designed such that the core of the dosage form will rapidly (immediately or catastrophically) disintegrate into an aqueous environment of use when non-acidic media or digestive juice in the environment come into contact with the core. The TR coating generally possesses erosion and/or diffusion properties that are essentially independent of the pH of the external aqueous medium and of the enzymes and bile salts present in the GI tract.
One embodiment of the invention provides a solid dosage form for providing a delayed and subsequently rapid release of omeprazole into an environment of use, wherein the dosage form comprises:
a core comprising omeprazole and at least one pharmaceutical excipient, wherein the core rapidly releases the omeprazole after the core is contacted with an aqueous fluid in an environment of use; and
a non-enteric water soluble time-release coating surrounding and in contact with the core, wherein the coating delays the contact of the core with the aqueous fluid in the environment of use for a sufficient period of time to delay the release of the omeprazole from the core, and the coating subsequently loses its physical integrity after the delay period thereby permitting the core to rapidly release the omeprazole into the environment of use.
Specific embodiments of the invention include those wherein: 1) the dosage form includes plural coated cores which are granules, beads, pellets, spheroids, microspheres, or seeds that are compressed into a tablet or filled into a capsule; 2) the core contains one or more osmotic agents that promote a buildup of osmotic pressure in the core and aid in disintegrating the core following contact with an aqueous fluid; 3) the osmotic agents are alkaline reacting compounds or additional pharmaceutical excipients known in the art for use in preparing cores of solid dosage forms; 4) a disintegrant is present in the core to ensure that the core disintegrates in aqueous media; 5) the time-release coating comprises one or more hydrophilic or hydrophobic polymers optionally containing one or more additives that regulate the strength of the film, as well as the erosion and/or diffusion properties of the film; 6) the dosage form is adapted for oral administration, the time-release coating is sufficiently thick to retain its chemical and physical integrity in the stomach, and the time-release coating loses its physical integrity in the upper portion of the GI tract downstream from the stomach; 7) the time-release coating comprises one or more electrolytes, clays, polysaccharides and/or other hydrophilic materials to influence the period of time that it takes for the external aqueous medium to reach the core containing the drug; 8) the time-release coating begins to erode shortly after administration to a patient and continues to erode for a period of at least 1 hour after which it loses its physical integrity and exposes the core to the environment of use thereby providing a delayed release of omeprazole; 9) the time-release coating does not erode to a major extent but permits the diffusion of an aqueous fluid therein and delays exposure of the core to the aqueous fluid for a period of at least 1 hour after which time the core rapidly disintegrates and the time-release coating loses its physical integrity; 10) the time-release coating is about 100-5000, or 250-1000 at least about 100, microns thick and delays the release of omeprazole from the core at least about 1 hour after administration; 11) the time-release coating delays the release of omeprazole from the core 1-3 hours after administration; 12) the time-release coating also contains one or more buffering agents and/or alkalizing agents; 13) the time-release coating also contains one or more erosion regulators and/or diffusion regulators; 14) the time-release coating is applied onto the core as a solution or suspension; and/or 15) the time-release coating is compressed onto the core.
Another aspect of the invention provides a method of administering omeprazole orally comprising the step of:
administering an oral solid pharmaceutical formulation consisting essentially of an omeprazole-containing core and a non-enteric time-release coating surrounding and in contact with the core, wherein the time-release coating delays release of the omeprazole for a period of about 0.5-5.0 hours after administration, after which the omeprazole is released rapidly from the core.
Specific embodiments of the invention also include those wherein: 1) the time-release coating delays the release of omeprazole from the core until expiration of about 1-3 hours after administration; 2) the omeprazole is released from the core over a period of about 0.1-120 minutes, or no more than 150 minutes, once the core is contacted with an aqueous fluid; 3) the core comprises a mixture of omeprazole and at least one pharmaceutical excipient; 4) the core comprises an inert substrate onto which is applied, by spraying or compression, a mixture comprising omeprazole and at least one pharmaceutical excipient; 5) the time-release coating delays the release of omeprazole in an approximately pH independent manner; 6) the dosage form provides an omeprazole duration of action of at least about 12 hours and is administered once or twice daily; 7) the dosage form provides an omeprazole duration of action of about 24 hours and is administered once daily; 8) the dosage form is used to treat GERD; 9) the dosage form is administered between meals; 10) the dosage form is administered during meals; 11) the dosage form is administered just prior to or just after a meal; 12) the time-release coating delays contact of the core with an aqueous fluid in the environment of use; 13) the time-release coating erodes after administration; 14) the time-release coating permits diffusion of an aqueous fluid therein after administration; and/or 15) the time-release coating comprises two or more adjacent layers of the composition comprising the time-release coating.
These and other aspects of this invention will be apparent upon reference to the following detailed description and attached figures. To that end, certain patents and other documents are cited herein to more specifically set forth various aspects of this invention. Each of these documents is hereby incorporated by reference in its entirety.